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Carol Fierke

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Primary Appointment: Graduate School
Other PIBS Depts.: Biophysics
PubMed Name: Carol A. Fierke
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  Our goal is to understand the mechanisms used by biological catalysts, both proteins and nucleic acids, to achieve high efficiency, stringent specificity and rigorous control. We are elucidating catalytic mechanisms, essential active site features, specificity and inhibition of metalloenzymes and ribozymes, including protein farnesyltransferase, UDP-3-O-acyl-GlcNAC deacetylase, histone deacetylase, protein palmitoyltransferase and ribonuclease P. These studies should enhance the design of potent inhibitors of these enzymes useful for the treatment of cancer or bacterial infections. In particular, we are investigating the role of proteins in modulating the reactivity of bound Zn(II) or Fe(II) and developing specific inhibitors that coordinate the active site metal. We are also investigating the molecular recognition of substrates leading to the in vivo specificity of protein prenylation, acetylation and palmitoylation using peptide and small molecule libraries as well as chemical biology methods to interrogate the intracellular reactions. Finally, we are elucidating the role of metal ions and protein/RNA interactions in ribonuclease P, a ribozyme/protein complex, using a variety of biophysical techniques, including NMR and time-resolved fluorescence. These studies are increasing our understanding of the catalytic modes used by ribozymes in comparison to protein catalysts.

Zinc, iron and copper ions are proposed to play important biological roles, especially in neurobiology, as well as playing important roles in the development of a number of diseases. Furthermore, a number of metals, such as lead and cadmium, are toxic. We are investigating the mechanisms of metal homeostasis and metal toxicity using a combination of biochemistry, genetics and imaging. To this end, we are redesigning the zinc metalloenzyme, carbonic anhydrase II, to optimize a fluorescent biosensor for measuring and imaging “readily exchangeable” metal ions in complex biological mixtures, such as cells, plasma and sea water and are developing similar sensors to measure cellular iron concentrations. Additionally, we are using X-ray fluorescence microprobe imaging to image total metal ions in wild-type and mutant yeast cells. Finally, we are examining the metal content and the mechanisms of metal insertion into proteins in vivo using biochemistry and analysis of libraries of deletion mutants. These studies should lead to a better understanding of the functions and regulation of biological transition metals.